Single-Pulse Activation of the Cholinergic Anti-Inflammatory Pathway to Treat Chronic Inflammation

ABSTRACT

Described herein are methods and systems for applying extremely low duty-cycle stimulation sufficient to treat chronic inflammation. In particular, described herein are single supra-threshold pulses of electrical stimulation sufficient to result in a long-lasting (e.g., &gt;4 hours, greater than 12 hours, greater than 24 hours, greater than 48 hours) inhibition of pro-inflammatory cytokines and/or effects of chronic inflammation. These methods and devices are particularly of interest in treatment of inflammatory bowel disease (IBD).

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/484,112, filed on May 9, 2011, which is hereby incorporated byreference in its entirety. This patent application may be related to anyof the following patent and pending U.S. application Ser. No.12/434,462, filed on May 1, 2009 and entitled “VAGUS NERVE STIMULATIONELECTRODES AND METHODS OF USE”; U.S. application Ser. No. 12/620,413,filed Nov. 17, 2009 and entitled “DEVICES AND METHODS FOR OPTIMIZINGELECTRODE PLACEMENT FOR ANTI-INFLAMMATORY STIMULATION”; U.S. applicationSer. No. 12/874,171, filed Sep. 1, 2010 and entitled “PRESCRIPTION PADFOR TREATMENT OF INFLAMMATORY DISORDERS”; U.S. application Ser. No.12/917,197, filed Nov. 1, 2010 and entitled “MODULATION OF THECHOLINERGIC ANTI-INFLAMMATORY PATHWAY TO TREATMENT OR ADDICTION”; U.S.application Ser. No. 12/978,250, filed Dec. 23, 2010 and entitled“NEURAL STIMULATION DEVICES AND SYSTEMS FOR TREATMENT OF CHRONICINFLAMMATION”; and U.S. application Ser. No. 12/797,452, filed Jun. 9,2010 and entitled “NERVE CUFF WITH POCKET FOR LEADLESS STIMULATOR.”

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference in their entirety to the sameextent as if each individual publication or patent application wasspecifically and individually indicated to be incorporated by reference.

FIELD OF THE INVENTION

The present invention relates generally to systems and devices fortreatment of disorders, including chronic inflammation and inflammatorydisorders using extremely low duty-cycle stimulation. In particular,described herein are systems, devices and methods for treating disorderssuch as intestinal inflammatory disorders. Further described hereingenerally are methods and devices, including an implantablemicrostimulators, adapted for electrically stimulating the vagus nerveto treat chronic inflammation by extremely low duty cycle stimulation tomodulate an inflammatory response (via the nicotinic cholinergicanti-inflammatory pathway).

BACKGROUND OF THE INVENTION

Electrical stimulation of the neural cholinergic anti-inflammatorypathway (CAP or NCAP) has been described in the literature, beginningwith the seminal work of Kevin Tracey (see, e.g., Tracey, K J“Physiology and immunology of the cholinergic antiinflammatory pathway.”The Journal of clinical investigation 2007:117 (2): 289-96), who firstidentified the cholinergic anti-inflammatory pathway and characterizedthe link between vagus nerve stimulation and inhibition of inflammationby suppressing cytokine production. Since then, research as continued toexplore the relationship between stimulation of the CAP and modulationof inflammatory disorders. Typical stimulation parameters have includestimulation by a burst of pulses (e.g., between 10 Hz to 1 GHz forbetween 30 sec and 20 min), with a slight increase in effect seen athigher frequencies (see, e.g., US 2009/0143831 to Huston et al.).

Although this work has suggested that chronic inflammation may besuccessfully treated by an implantable stimulator, the design andimplementation of such a chronically implantable and usable stimulatorhas proven elusive, in part because of the power demands that a devicecapable of truly long-term, chronic, usage would face.

Implantable electrical stimulation devices have been developed fortherapeutic treatment of a wide variety of diseases and disorders. Forexample, implantable cardioverter defibrillators (ICDs) have been usedin the treatment of various cardiac conditions. Spinal cord stimulators(SCS), or dorsal column stimulators (DCS), have been used in thetreatment of chronic pain disorders including failed back syndrome,complex regional pain syndrome, and peripheral neuropathy. Peripheralnerve stimulation (PNS) systems have been used in the treatment ofchronic pain syndromes and other diseases and disorders. Functionalelectrical stimulation (FES) systems have been used to restore somefunctionality to otherwise paralyzed extremities in spinal cord injurypatients.

Recently, implantable vagus nerve stimulations have been developed,including vagus nerve stimulators to treat inflammation. Such implantstypically require an electrode and a power source. The size anduse-limiting parameters may typically be the power requirements, whicheither require a long-lasting (and therefore typically large) battery,or require the added complication of charging circuitry and chargingdevices.

For example, typical implantable electrical stimulation systems mayinclude one or more programmable electrodes on a lead that are connectedto an implantable pulse generator (IPG) that contains a power source andstimulation circuitry. Even relatively small implantable neuralstimulator technology, i.e. microstimulators, having integral electrodesattached to the body of a stimulator may share some of thesedisadvantages, as the currently developed leadless devices tend to belarger and more massive than desirable, making it difficult to stablyposition such devices in the proper position with respect to the nerve.

We herein describe the surprising result that long-lasting, robustinhibition of inflammation may be achieved by on a single (or very few)supra-threshold electrical pulse applied to the vague nerve. Thisfinding is particularly surprising given the extraordinarily robusteffect despite the minimal power applied, particularly compared topublished data showing effects at much higher applied energy. Thesefindings support various extremely low-power devices, system and methodsfor treating chronic inflammation. In particular, devices and methodsfor the treatment of inflammatory disorders, including inflammatorydisorders of the intestine (e.g., irritable bowel disorder or IBD) aredescribed, including microstimulators and methods of using them based onthe remarkably low power requirements identified.

SUMMARY

Described herein are devices, systems and methods for theextraordinarily low duty cycle stimulation of the vagus nerve. Anextraordinarily low, extremely low, super low, or ultra low duty cyclerefers generally to a duty cycle that provides stimulation using both alow number of electrical pulses per time period and a low stimulationintensity such that power requirements of the duty cycle are very low.The following are examples of various embodiments of extraordinarilylow, extremely low, super low, or ultra low duty cycles. In someembodiments, the number of electrical pulses can be between 1 and 5, inone pulse increments, every 4 to 48 hours, in 4 hour increments. In someembodiments, the stimulation intensity can be at a supra-threshold levelthat is capable of effecting the desired physiological response throughthe vagus nerves. In some embodiments, the supra-threshold level isbetween about 100 μA and 5000 μA, or between about 100 μA and 4000 μA,or between about 100 μA and 3000 μA, or between about 100 μA and 2000μA. In some embodiments, the supra-threshold level is less than about2000 μA, 3000 μA, 4000 μA or 5000 μA.

In some embodiments, the duty cycle is one supra-threshold pulse every 4hours, with the pulse amplitude less than about 2000 μA. In someembodiments, the duty cycle is one pulse every 4 hours, with the pulseamplitude less than about 3000 μA. In some embodiments, the duty cycleis one pulse every 12 hours, with the pulse amplitude less than about2000 μA. In some embodiments, the duty cycle is one pulse every 12hours, with the pulse amplitude less than about 3000 μA. In someembodiments, the duty cycle is one pulse every 24 hours, with the pulseamplitude less than about 2000 μA. In some embodiments, the duty cycleis one pulse every 24 hours, with the pulse amplitude less than about3000 μA. In some embodiments, the duty cycle is one pulse every 48hours, with the pulse amplitude less than about 2000 μA. In someembodiments, the duty cycle is one pulse every 48 hours, with the pulseamplitude less than about 3000 μA.

In some embodiments the pulse width can be between about 100 to 1000 μS,or can be about or less than about 100, 200, 300, 400, 500, 600, 700,800, 900 or 1000 μS. In some embodiments, the frequency can be about orless than about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 Hz. In someembodiments, the IPI can be about or less than about 100, 200, 300, 400,500, 600, 700, 800, 900 or 1000 μS.

In some embodiments, a system for treating chronic inflammation and/oran inflammatory disorder in a patient is provided. The system includesan implantable microstimulator configured to apply a low duty-cyclestimulation to a vagus nerve, wherein the low duty-cycle stimulationprovides no more than a single supra-threshold pulse every four hours;and a controller configured to set a dose for the microstimulatorwherein the dose comprises the single supra-threshold pulse followed byan off-period of at least four hours. In some embodiments, theoff-period is at least 24 hours, or at least 48 hours, or between about4 to 48 hours, or between about 12 to 48 hours, or between about 24 to48 hours. In some embodiments, the single supra-threshold pulse has apulse amplitude of less than 5 mA, less than 3 mA, or less than 2 mA. Insome embodiments, the single supra-threshold pulse is biphasic. In someembodiments, the chronic inflammation is intestinal inflammation. Insome embodiments, the chronic inflammation is inflammatory boweldisease. In some embodiments, the chronic inflammation is Crohn'sdisease.

In some embodiments, a method of treating chronic inflammation and/orinflammatory disorders in a patient is provided. The method includesimplanting a microstimulator; and applying only a single supra-thresholdstimulus pulse from the microstimulator to the vagus nerve followed byan off-time of at least 4 hours. In some embodiments, the off-time is atleast 24 hours, at least 48 hours, or between about 4 to 48 hours, orbetween about 12 to 48 hours, or between about 24 to 48 hours. In someembodiments, the single supra-threshold stimulus pulse has a pulseamplitude of less than 5 mA, less than 3 mA, or less than 2 mA. In someembodiments, the single supra-threshold stimulus pulse is biphasic. Insome embodiments, the chronic inflammation is intestinal inflammation.In some embodiments, the chronic inflammation is inflammatory boweldisease. In some embodiments, the chronic inflammation is Crohn'sdisease.

Types of inflammatory disorders that may be treated as described hereininclude a variety of disease states, including diseases such as hayfever, atherosclerosis, arthritis (rheumatoid, bursitis, goutyarthritis, polymyalgia rheumatic, etc.), asthma, autoimmune diseases,chronic inflammation, chronic prostatitis, glomerulonephritis,nephritis, inflammatory bowel diseases, pelvic inflammatory disease,reperfusion injury, transplant rejection, vasculitis, myocarditis,colitis, etc.

Non-limiting examples of inflammatory disorders which can be treatedusing the present invention include appendicitis, peptic ulcer, gastriculcer, duodenal ulcer, peritonitis, pancreatitis, ulcerative colitis,pseudomembranous colitis, acute colitis, ischemic colitis,diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitits,hepatitis, Crohn's disease, enteritis, Whipple's disease, allergy,anaphylactic shock, immune complex disease, organ ischemia, reperfusioninjury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock,cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis,sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis,urethritis, bronchitis, emphysema, rhinitis, pneumonitits,pneumoultramicroscopic silicovolcanoconiosis, alvealitis, bronchiolitis,pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virusinfection, HIV infection, hepatitis B virus infection, hepatitis C virusinfection, herpes virus infection disseminated bacteremia, Dengue fever,candidiasis, malaria, filariasis, amebiasis, hydatid cysts, burns,dermatitis, dermatomyositis, sunburn, urticaria, warts, wheals,vasulitis, angiitis, endocarditis, arteritis, atherosclerosis,thrombophlebitis, pericarditis, myocarditis, myocardial ischemia,periarteritis nodosa, rheumatic fever, Alzheimer's disease, coeliacdisease, congestive heart failure, adult respiratory distress syndrome,meningitis, encephalitis, multiple sclerosis, cerebral infarction,cerebral embolism, Guillame-Barre syndrome, neuritis, neuralgia, spinalcord injury, paralysis, uveitis, arthritides, arthralgias,osteomyelitis, fasciitis, Paget's disease, gout, periodontal disease,rheumatoid arthritis, synovitis, myasthenia gravis, thyroiditis,systemic lupus erythematosis, Goodpasture's syndrome, Behcet's syndrome,allograft rejection, graft-versus-host disease, Type I diabetes, Type IIdiabetes, ankylosing spondylitis, Berger's disease, Reiter's syndrome,Hodgkin's disease, ileus, hypertension, irritable bowel syndrome,myocardial infarction, sleeplessness, anxiety and stent thrombosis.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe claims that follow. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 is a diagram of a single stimulation waveform;

FIG. 2 is a graph comparing the effect on TNF levels from a singlestimulation pulse with the effect from up to 3000 pulses;

FIG. 3 is a graph illustrating the effect on TNF levels from a singlestimulation pulse 24 hours post-stimulation;

FIG. 4 is a graph illustrating the effect on TNF levels from a singlestimulation pulse 3 hours and 24 hours post-stimulation;

FIG. 5 is a graph illustrating the effect on lesion area in a rat modelof IBD from a single stimulation pulse; and

FIG. 6 is a graph illustrating the long term effect on lesion area in arat model of IBD from a single stimulation pulse.

DETAILED DESCRIPTION

In general, described herein are systems, methods and devicesillustrating extraordinarily low duty cycle stimulation of the vagusnerve to treat a disorder. In particular, described herein are systems,methods and devices illustrating extraordinarily low duty cyclestimulation of the vagus nerve to reduce or prevent inflammation and theeffects of inflammation in a mammalian model. An extraordinarily low,extremely low, super low, or ultra low duty cycle refers generally to aduty cycle that provides stimulation using both a low number ofelectrical pulses per time period and a low stimulation intensity suchthat power requirements of the duty cycle are very low. The methodsdescribed herein apply various stimulation protocols that may be used tosignificantly reduce inflammation and/or the effects of inflammation.Simulation parameters that may be varied include the pulse shape (e.g.,sinusoidal, square, biphasic, monophasic, etc.) the duration ofstimulation, the on-time, the off-time, the inter-pulse interval, or thelike. One key factor examined herein is the number of supra-thresholdpulses. As shown herein, the stimulation of the vagus nerve with even asingle supra-threshold stimulus results in a significant andlong-lasting effect, even when compared to multiple stimulations. Thiseffect was particularly profound when examined using a rodent model forIBD.

The following are examples of various embodiments of extraordinarilylow, extremely low, super low, or ultra low duty cycles. In someembodiments, the number of electrical pulses can be between 1 and 5, inone pulse increments, every 4 to 48 hours, in 4 hour increments. In someembodiments, the stimulation intensity can be at a supra-threshold levelthat is capable of effecting the desired physiological response throughthe vagus nerves. In some embodiments, the supra-threshold level isbetween about 100 μA and 5000 μA, or between about 100 μA and 4000 μA,or between about 100 μA and 3000 μA, or between about 100 μA and 2000μA. In some embodiments, the supra-threshold level is less than about2000 μA, 3000 μA, 4000 μA or 5000 μA.

In some embodiments, the duty cycle is one supra-threshold pulse every 4hours, with the pulse amplitude less than about 2000 μA. In someembodiments, the duty cycle is one pulse every 4 hours, with the pulseamplitude less than about 3000 μA. In some embodiments, the duty cycleis one pulse every 12 hours, with the pulse amplitude less than about2000 μA. In some embodiments, the duty cycle is one pulse every 12hours, with the pulse amplitude less than about 3000 μA. In someembodiments, the duty cycle is one pulse every 24 hours, with the pulseamplitude less than about 2000 μA. In some embodiments, the duty cycleis one pulse every 24 hours, with the pulse amplitude less than about3000 μA. In some embodiments, the duty cycle is one pulse every 48hours, with the pulse amplitude less than about 2000 μA. In someembodiments, the duty cycle is one pulse every 48 hours, with the pulseamplitude less than about 3000 μA.

The examples described herein use a stimulator and stimulation controlpackage that was developed for use in driving vagus nerve stimulation.In some example, the stimulation is controlled by a software packagethat is configured to run on a microprocessor (e.g., personal computer)and to control output of an emulator/stimulator (which may be referredto as an “ITE” or integrated terminal emulator). Thus, the systemsdescribed herein may include logic (e.g., control logic) that may besoftware, firmware, and/or hardware to control the application ofstimulation. For example, in some variations, the parameters controllingstimulation and data acquisition may include: (1) selected stimulatingelectrode pair including a cathode and anode; (2) frequency in 1 Hzincrements; (3) Pulse Width (PW): 20-2,000 uS in 1 uS increments; (4)Pulse Amplitude (PA): ±0-5,000 uA in 3 uA increments; and (5)Inter-Pulse-Interval between phase A & B of waveform (IPI): 20-2,000 uSin 1 uS increments.

In addition to the exemplary parameters provided above, in someembodiments the PW can be between about 100 to 1000 μS, or can be aboutor less than about 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000μS. In some embodiments, the frequency can be about or less than about10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 Hz. In some embodiments, theIPI can be about or less than about 100, 200, 300, 400, 500, 600, 700,800, 900 or 1000 μS.

For example, the exemplary waveform shown on FIG. 1 is a biphasic(charge balanced) waveform 100 that includes two symmetric pulse widths102 (PW) separated by an inter-pulse interval 104 (IPI). The pulsewidths 102 have a pulse amplitude 106 (PA) that is also symmetric forthe first phase 108 (phase A) and the second phase 110 (phase B) of thebiphasic stimulus, with a negative pulse amplitude in phase A and apositive amplitude in phase B. Other pulse waveforms may be used. Insome embodiments, the pulse waveforms may be non-biphasic and/or mayhave asymmetric pulse widths and/or asymmetric pulse amplitudes.

The stimulator may generate a pulse train on a pair of electrodes. Thepulses may be generated using a bipolar current source and can becapacitively isolated with >1 uF ceramic capacitors on both electrodesoutputs. Compliance voltage can be set to as high as +/−18.8 volts.

The different experimental examples described herein show thatappropriate NCAP stimulation of the vagus nerve can be used to limit oreliminate the effects of intestinal inflammation, in particular in a ratmodel of colitis and a rat model of Crohn's disorder. Based on thisdata, a biphasic simulation at the parameters described above maysuccessfully treat intestinal inflammation.

In one example, mice (Male, BALB/c) were anesthetized and cuffelectrodes (0.3 mm ID, 0.5 mm inter-electrode distance; Microprobes,Gaithersburg, Md.) were placed around the left carotid sheath(containing the cervical vagus nerve) and secured by suture.Supra-threshold pulses (750 μA, 200 μS, 10 Hz) were applied in variousnumbers (0, 1, 10, 100, 300, 600, 3000). Afterwards, the electrode wasremoved and the wound stapled closed. Mice recovered for 3 hours, andthen were challenged with LPS (5 mg/kg; IP); these mice were sacrificed90 minutes post-LPS and serum TNF measured by ELISA to measure theeffects on inflammatory cytokines. As shown on FIG. 2, even a singlesupra-threshold stimulus resulted in a significant suppression of TNF at3 hours after treatment. Thus, the effect was long lasting and theeffect from a single pulse at 3 hours was equivalent to the effectgenerated by up to 3000 pulses.

A second similar experiment was conducted to examine the long lastingeffect of a single supra-threshold pulse on the cholinergicanti-inflammatory pathway (CAP). Mice (Male, BALB/c) were anesthetizedand cuff electrodes (0.3 mm ID, 0.5 mm inter-electrode distance;Microprobes, Gaithersburg, Md.) were placed around the left carotidsheath (containing the cervical vagus nerve) and secured by suture.Supra-threshold pulses (750 gA, 2000, 10 Hz) were applied in variousnumbers (0, 1, 600). Afterwards, the electrode was removed and the woundstapled closed. Mice recovered for 24 hours, and then were challengedwith LPS (5 mg/kg; IP); these mice were sacrificed 90 minutes post-LPSand serum TNF measured by ELISA to measure the effects on inflammatorycytokines. As shown on FIG. 3, a single supra-threshold stimulusresulted in a significant suppression of TNF at 24 hours after treatmentthat was equivalent to the effect generated by 600 pulses.

FIG. 4 combines selected portions of the results of the two experimentsdescribed above to show that single pulse stimulation of the NCAPeffects suppression of LPS-inducible TNF at 3 hours and 24 hourspost-stimulation at the same effectiveness as 600 pulses.

In another example, an experiment was conducted to determine theeffectiveness of single pulse suppression of lesion area in a rat modelfor IBD/Crohn's disease. Rats were anesthetized and were either given asham stimulation or a single supra-threshold stimulus to the leftcervical vagus nerve (1 pulse at 750 μA, 2000 pulse width, 10 Hz). IBDwas induced at 30 minutes post-stimulation by the SC injection ofindomethacin (10 mg/kg (5 mg/mL) in 5% sodium bicarbonate). Lesions werestained in-life 23.5 hours post-indomethacin injection by anesthetizingthe rats with isoflurane and IV tail injection with Evans Blue (0.3 mlof 1%). Rats were sacrificed via C02 asphyxiation at 24 hours postdisease induction, and the small intestines were harvested, cleaned andfixed in 2% formalin overnight. Photographs were taken and digitized ofthe fixed intestines and lesions were quantified by a blinded scorer. Asillustrated in FIG. 5, a single supra-threshold stimulus (750 μA, 200 μSpulse width, 10 Hz) resulted in a profound reduction in lesions.

These results are even more significant, given the data shown in FIG. 6,which illustrates a “memory effect” of vagus nerve stimulation in a ratmodel of Crohn's disease. Rats were anesthetized and were either given asham stimulation or an actual stimulation to the left cervical vagusnerve (1 mA, 200 μS pulse width, 10 Hz, 60 s). IBD/Crohn's disease wasinduced at various times (see FIG. 6) post-stimulation by the SCinjection of indomethacin (10 mg/kg (5 mg/mL) in 5% sodium bicarbonate).Lesions were stained in-life 23.5 hours post-disease induction byanesthetizing the rats with isoflurane and IV tail injection with EvansBlue (0.3 ml of 1%). Rats were sacrificed via C02 asphyxiation at 24hours post disease induction, and the small intestines were harvested,cleaned and fixed in 2% formalin overnight. Photographs were taken anddigitized of the fixed intestines and lesions were quantified by ablinded scorer. In this example, a brief period of stimulation of thevagus nerve may result in a surprisingly long-lasting effect (e.g., upto 48 hours) in the reduction of intestinal lesions otherwise induced bythe application of indomethacin. This data strongly suggests thatstimulation may be provided extremely infrequently, with long (e.g., >48hours) of “silent” periods without stimulation applied. Such extremelylow duty-cycle stimulation for treating IBD may be particularly helpfulin implantable systems, allowing extremely long battery life whilehaving unexpectedly robust therapeutic benefits.

Although the examples provided above describe methods, systems anddevices for treating an inflammatory disorder in a rat model, all themethods, systems and devices described herein can be used and/or adaptedfor use in other mammals, such as humans. For example, a system andmethod for treating an inflammatory disorder in a human using a singlesupra-threshold pulse and/or an extraordinarily low duty cyclestimulation protocol can include an electrode, such as a cuff electrode,that is configured to be implanted around the vagus nerve and deliverelectrical stimulation to the vagus nerve of the patient. The system canfurther include a processor, memory for storing instructions, and/or acontroller can include programming to deliver the low duty cyclestimulation protocol, including the single supra-threshold pulseprotocol, to the vagus nerve via the cuff electrode. A battery can beprovided to provide power for the system, and because the low duty cyclestimulation protocol consumes so little energy, the battery life can begreatly extended, allowing the system to be completely implanted withinthe patient for a long duration before the battery needs to be replacedor recharged. For an implanted system, this provides a great benefitsince it can reduce the frequency of surgical procedures that may berequired to change the battery.

The stimulation parameters used in this system can be the same orsimilar to the parameters disclosed above. For example, the pulseamplitude can be less than about 5, 4, 3, or 2 mA. In addition, the lowduty cycle stimulation protocol can deliver a single supra-thresholdpulse between off-times of between about 4 to 48 hours, or at least 4,12, 24, or 48 hours. In some embodiments the pulse width can be betweenabout 100 to 1000 μS, or can be about or less than about 100, 200, 300,400, 500, 600, 700, 800, 900 or 1000 μS. In some embodiments, thefrequency can be about or less than about 10, 20, 30, 40, 50, 60, 70,80, 90 or 100 Hz. In some embodiments, the IPI can be about or less thanabout 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 μS.

In general, these results suggest that the application of even a singlebrief supra-threshold stimulus of the vagus nerve may result in asubstantial reduction in the effects of inflammation, possibly byinhibition of inflammatory cytokines such as TNF. These results are bothsurprising, given the prior arts tendency to stimulate for much longertimes, and important for the design of future devices and methods. Inparticular, stimulation of the vagus nerve (or other portions of theinflammatory reflex) may be configured to apply extremely low duty-cyclestimulation. As mentioned briefly, this would allow for much smaller,lighter and more efficient implantable stimulation systems.

Types of inflammatory disorders that may be treated as described hereininclude a variety of disease states, including diseases such as hayfever, atherosclerosis, arthritis (rheumatoid, bursitis, goutyarthritis, polymyalgia rheumatic, etc.), asthma, autoimmune diseases,chronic inflammation, chronic prostatitis, glomerulonephritis,nephritis, inflammatory bowel diseases, pelvic inflammatory disease,reperfusion injury, transplant rejection, vasculitis, myocarditis,colitis, etc.

Non-limiting examples of inflammatory disorders which can be treatedusing the present invention include appendicitis, peptic ulcer, gastriculcer, duodenal ulcer, peritonitis, pancreatitis, ulcerative colitis,pseudomembranous colitis, acute colitis, ischemic colitis,diverticulitis, epiglottitis, achalasia, cholangitis, cholecystitits,hepatitis, Crohn's disease, enteritis, Whipple's disease, allergy,anaphylactic shock, immune complex disease, organ ischemia, reperfusioninjury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock,cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis,sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis,urethritis, bronchitis, emphysema, rhinitis, pneumonitits,pneumoultramicroscopic silicovolcanoconiosis, alvealitis, bronchiolitis,pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virusinfection, HIV infection, hepatitis B virus infection, hepatitis C virusinfection, herpes virus infection disseminated bacteremia, Dengue fever,candidiasis, malaria, filariasis, amebiasis, hydatid cysts, burns,dermatitis, dermatomyositis, sunburn, urticaria, warts, wheals,vasulitis, angiitis, endocarditis, arteritis, atherosclerosis,thrombophlebitis, pericarditis, myocarditis, myocardial ischemia,periarteritis nodosa, rheumatic fever, Alzheimer's disease, coeliacdisease, congestive heart failure, adult respiratory distress syndrome,meningitis, encephalitis, multiple sclerosis, cerebral infarction,cerebral embolism, Guillame-Barre syndrome, neuritis, neuralgia, spinalcord injury, paralysis, uveitis, arthritides, arthralgias,osteomyelitis, fasciitis, Paget's disease, gout, periodontal disease,rheumatoid arthritis, synovitis, myasthenia gravis, thyroiditis,systemic lupus erythematosis, Goodpasture's syndrome, Behcet's syndrome,allograft rejection, graft-versus-host disease, Type I diabetes, Type IIdiabetes, ankylosing spondylitis, Berger's disease, Reiter's syndrome,Hodgkin's disease, ileus, hypertension, irritable bowel syndrome,myocardial infarction, sleeplessness, anxiety and stent thrombosis.

Any of these disorders (e.g., inflammatory disorders) may be treated by,for example, implanting a cuff electrode around the vagus nerve, andusing an extraordinarily low duty cycle stimulation protocol asdescribed herein to treat. A processor and memory for storinginstructions and/or programming can be used to control the stimulationprotocol. The stimulation parameters used in this system and method canbe the same or similar to the parameters disclosed above. For example,the pulse amplitude of the single supra-threshold pulse can be less thanabout 5, 4, 3, or 2 mA. In addition, the low duty cycle stimulationprotocol can deliver a single supra-threshold pulse between off-times ofbetween about 4 to 48 hours, or at least 4, 12, 24, or 48 hours. Any ofthese methods may include a step of determining the efficacy of thetreatment. For example, any of these methods may include the step ofmonitoring the patient before and/or during treatment. For example, intreating an inflammatory disorder, a biomarker for inflammation may bemonitored, such as a cytokine or other marker. In some variations,monitoring the patient may include assessing the patient visually (e.g.,for swelling, body temperature, etc.). In some variations the systemsdescribed herein may include a sensor and/or data processing subsystemfor monitoring the patient and/or the effect of the treatment with thesystem.

Although the examples and description above focuses primarily oninflammatory disorders, in some embodiment, the systems, devices andmethods described herein can be used to treat non-inflammatory diseasesor disorders. For example, the systems, devices and methods describedherein can be used to activate, regulate, and/or modulate the levels ofsirtuins by extraordinarily low duty cycle stimulation of the vagusnerve. The modulation of sirtuins by vagus nerve stimulation is alsodiscussed in U.S. application Ser. No. 13/338,185, filed Dec. 27, 2011and entitled “MODULATION OF SIRTUINS BY VAGUS NERVE STIMULATION,” whichis hereby incorporated by reference in its entirety for all purposes. Asabove, a cuff electrode can be implanted around the vagus nerve and aprocessor and memory for storing instructions and/or programming can beused to control the stimulation protocol. The stimulation parametersused in this system and method can be the same or similar to theparameters disclosed above. For example, the pulse amplitude of thesingle supra-threshold pulse can be less than about 5, 4, 3, or 2 mA. Inaddition, the low duty cycle stimulation protocol can deliver a singlesupra-threshold pulse between off-times of between about 4 to 48 hours,or at least 4, 12, 24, or 48 hours. In some embodiments the pulse widthcan be between about 100 to 1000 μS, or can be about or less than about100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 μS. In someembodiments, the frequency can be about or less than about 10, 20, 30,40, 50, 60, 70, 80, 90 or 100 Hz. In some embodiments, the IPI can beabout or less than about 100, 200, 300, 400, 500, 600, 700, 800, 900 or1000 μS.

As mentioned above, in some embodiments, the system, device, and/ormethod includes monitoring the effects of the stimulation on the diseasebeing treated. For example, inflammation indicators or diseaseindicators or other indicators can be monitored to evaluate the efficacyof the treatment protocol, allowing the stimulation protocol to beadjusted based on the evaluation. Any one of the parameters describedherein can be modulated based on the evaluation. For example, the pulseamplitude and/or the off time can be increased or decreased to optimizethe treatment efficacy. Examples of indicators that can be monitoredinclude TNF levels, lesion size, degree or level of inflammation,cytokine levels, pain levels, sirtuin levels, and the like.

Variations and modifications of the devices and methods disclosed hereinwill be readily apparent to persons skilled in the art. As such, itshould be understood that the foregoing detailed description and theaccompanying illustrations, are made for purposes of clarity andunderstanding, and are not intended to limit the scope of the invention,which is defined by the claims appended hereto. Any feature described inany one embodiment described herein can be combined with any otherfeature of any of the other embodiments whether preferred or not.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference for allpurposes.

1. A system for treating chronic inflammation in a patient, the systemcomprising: an implantable microstimulator configured to apply a lowduty-cycle stimulation to a vagus nerve, wherein the low duty-cyclestimulation provides no more than a single supra-threshold pulse everyfour hours; and a controller configured to set a dose for themicrostimulator wherein the dose comprises the single supra-thresholdpulse followed by an off-period of at least four hours.
 2. The system ofclaim 1, wherein the off-period is at least 24 hours.
 3. The system ofclaim 1, wherein the off-period is at least 48 hours.
 4. The system ofclaim 1, wherein the single supra-threshold pulse has a pulse amplitudeof less than 5 mA.
 5. The system of claim 1, wherein the singlesupra-threshold pulse has a pulse amplitude of less than 3 mA.
 6. Thesystem of claim 1, wherein the single supra-threshold pulse has a pulseamplitude of less than 2 mA.
 7. The system of claim 1, wherein thesingle supra-threshold pulse is biphasic.
 8. The system of claim 1,wherein the chronic inflammation is intestinal inflammation.
 9. Thesystem of claim 1, wherein the chronic inflammation is inflammatorybowel disease.
 10. The system of claim 1, wherein the chronicinflammation is Crohn's disease.
 11. A method of treating chronicinflammation in a patient, the method comprising: implanting a microstimulator; and applying only a single supra-threshold stimulus pulsefrom the microstimulator to the vagus nerve followed by an off-time ofat least 4 hours.
 12. The method of claim 11, wherein the off-time is atleast 24 hours.
 13. The method of claim 11, wherein the off-time is atleast 48 hours.
 14. The method of claim 11, wherein the singlesupra-threshold stimulus pulse has a pulse amplitude of less than 5 mA.15. The method of claim 11, wherein the single supra-threshold stimuluspulse has a pulse amplitude of less than 3 mA.
 16. The method of claim11, wherein the single supra-threshold stimulus pulse has a pulseamplitude of less than 2 mA.
 17. The method of claim 11, wherein thesingle supra-threshold stimulus pulse is biphasic.
 18. The method ofclaim 11, wherein the chronic inflammation is intestinal inflammation.19. The method of claim 11, wherein the chronic inflammation isinflammatory bowel disease.
 20. The method of claim 11, wherein thechronic inflammation is Crohn's disease.